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Non-invasive measurement of analytesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo TestingNon-invasive measurement of analytes description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070020181, Non-invasive measurement of analytes. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This invention is a continuation in part of U.S. Ser. No. 10/617,915, filed on Jul. 10, 2003, which is a continuation in part of U.S. Ser. No. 10/616,533, filed on Jul. 9, 2003, which claims priority to U.S. provisional patent application Ser. No. 60/425,488, filed Nov. 12, 2002, and this application also claims priority to Ser. No. 60/438,837, filed Jan. 9, 2003, Ser. No. 60/439,395, filed Jan. 10, 2003, Ser. No. 60/447,603, filed Feb. 13, 2003, and Ser. No. 60/______, filed on Oct. 31, 2003, each of which is incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] This invention provides devices, compositions and methods for determining the concentration of one or more metabolites or analytes in a biological sample, including cells, tissues, organs, organisms, and biological fluids. In particular, this invention provides materials, apparatuses, and methods for several non-invasive techniques for the determination of in vivo blood glucose concentration levels based upon the in vivo measurement of one or more biologically active molecules found in skin. BACKGROUND OF THE INVENTION [0003] Identifying and understanding the risk factors associated with diabetes is invaluable for the development and evaluation of effective intervention strategies. [0004] Lacking normal regulatory mechanisms, diabetics are encouraged to strive for optimal control through a modulated life style approach that focuses on dietary control, exercise, and glucose self-testing with the timely administration of insulin or oral hypoglycemic medications. Invasive forms of self-testing are painful and fraught with a multitude of psychosocial hurdles, and are resisted by most diabetics. Alternatives to the currently available invasive blood glucose testing are highly desirable. [0005] Conventional approaches to non-invasive alternatives seek to reduce or eliminate the skin trauma, pain, and blood waste associated with traditional invasive glucose monitoring technologies. In general, though never effectively demonstrated prior to this invention, noninvasive optical blood glucose monitoring requires no bodily fluid samples be withdrawn from tissue and involves external irradiation with electromagnetic radiation and measurement of the resulting optical flux (e.g., fluorescence or diffuse reflectance). In theory, but not in practice, glucose levels would be derived from the spectral information following comparison to reference spectra for glucose and background interferants, reference calibrants, and/or application of advanced signal processing mathematical algorithms. [0006] Radiation-based technologies, which are often referred to as potential candidates for solving the non-invasive glucose problem, have included variations of sampling and data processing methods including: 1) mid-infrared (MIR) spectroscopy, 2) near-infrared radiation (NIR) spectroscopy, 3) radio wave impedance, 4) autofluorescence and white light scattering, and 5) Raman spectroscopy. Each of these methods uses optical sensors and relies on the premise that the absorption or fluorescence pattern of electromagnetic radiation can be quantitatively related to a change in blood glucose concentration. However, other endogenous substances including, but not limited to, water, lipids, proteins, and hemoglobin are known to absorb energy, particularly infrared light and can easily obscure the relatively weak glucose signal. [0007] Other approaches to non-invasive glucose measurements are based on microvascular changes in the retina, acoustical impedance, nuclear magnetic resonance (NMR) spectroscopy and optical hydrogels that quantify glucose levels in tear fluid. While putatively non-invasive, these technologies have yet to be demonstrated as effective in clinical testing. [0008] Nearly noninvasive techniques tend to rely on interstitial fluid extraction from skin. This can be accomplished using permeability enhancers, sweat inducers, and/or suction devices with or without the application of electrical current. One device recently approved by the FDA relies on reverse iontophoresis, utilizing an electrical current applied to the skin. The current pulls out salt, which carries water, which, in turn, carries glucose. The glucose concentration of this recovered fluid is measured and is proportional to that of blood. In keeping with its nearly noninvasive description, this technology is commonly associated with some discomfort and requires at least twice daily calibrations against conventional blood glucose measurements (e.g. invasive lancing). [0009] Other nearly noninvasive blood glucose monitoring techniques similarly involve transcutaneous harvesting for interstitial fluid measurement. Other technologies for disrupting the skin barrier to obtain interstitial fluid include: 1) dissolution with chemicals; 2) microporation with a laser; 3) penetration with a thin needle; and/or 4) suction with a pump. Minimally invasive blood glucose monitoring can also involve the insertion of an indwelling glucose monitor under the skin to measure the interstitial fluid glucose concentration. These monitors typically rely on optical or enzymatic sensors. Although technologically innovative, these in situ sensors have had limited success. Implantable glucose oxidase ("GO") sensors have been limited by local factors causing unstable signal output, whereas optical sensors must overcome signal obfuscation by blood constituents as well as interference by substances with absorption spectra similar to glucose. Moreover, inflammation associated with subcutaneous monitoring may contribute to systematic errors requiring repositioning, recalibration or replacement, and more research is needed to evaluate the effects of variable local inflammation at the sensor implantation site on glucose concentration and transit time. [0010] Interstitial fluid glucose concentrations have previously been shown to be similar to simultaneously measured fixed or fluctuating blood glucose concentrations. See, e.g., Bantle et al., Journal of Laboratory and Clinical Medicine 130:436-441, 1997; Sternberg et al., Diabetes Care 18:1266-1269, 1995. Such studies helped validate noninvasive/minimally invasive technologies for blood glucose monitoring, insofar as many of these technologies measure glucose in blood as well as interstitial fluid. [0011] A noninvasive glucose monitor that is portable, simple and rapid to use, which provides accurate clinical information is desirable. In particular, the ability to derive first and second order information in real-time for dynamic glucose metabolism, such as the direction and rate of change of bioavailable glucose distributed within the blood and interstitial fluid space, would be extremely important for continuous and discrete glucose monitoring. SUMMARY OF THE INVENTION [0012] The methods and compositions of the present invention effectively determine the glucose concentration in blood for a living organism by non-invasive, in vivo measurement of the glucose level in skin by means of fluorescence measurements of metabolic indicators/reporters of glucose metabolism. Disclosed are dyes used as metabolic indicators that allow for specific in vivo monitoring of metabolites, which are used as indicators of metabolic activity. Dyes characterized by this invention are referred to herein as a small molecule metabolite reporters ("SMMRs"). [0013] This invention also provides for fluorescence measurements of extracellular and intracellular reporter molecules placed into the cytosol, nucleus, or organelles of cells within intact, living, tissue that track the concentration of blood glucose in an organism. When any one of a series of metabolites is measured using this technique, the molar concentration of blood glucose can be calculated. Direct or indirect fluorescence measurements of glucose using one or more of the following measurements is described: pH (as lactate/H.sup.+), membrane reduction-oxidation electric potential, NAD(P)H (nicotinamide adenine dinucleotide (phosphate), reduced form) for energy transfer, FAD.sup.+ (flavin adenine dinucleotide, oxidized form) for energy transfer, ATP/ADP ratio, Ca.sup.2+-pumping rate, Mg.sup.2+-pumping rate, Na.sup.+-pumping rate, K.sup.+-pumping rate, and vital mitochondrial membrane stains/dyes/molecules fluorescence response. These analytes, measured in skin using the techniques taught herein, are used to provide a complete picture of epidermal skin glycolytic metabolism where local epidermal analyte (glucose) quantities are proportional to the concentration of glucose in systemic blood, specifically the capillary fields within the papillary layer of the dermis (corium). Temperature and/or nitric oxide measurement may also be combined with the above measurements for better calibration and determination of glucose concentrations. [0014] The invention further provides sensor compositions that are applied to at least one surface of living tissue, organs, interstitial fluid, and whole organisms and transported into the tissue at an effective concentration. The sensor composition can include at least one small molecule metabolic reporter (SMMR) at an effective concentration such that when the at least one SMMR is brought in contact with one or more specific metabolites or analytes, a change in fluorescence or absorption occurs, thereby allowing quantification of the change in fluorescence or absorption. [0015] For example, the at least one small molecule metabolic reporter used in the sensor composition can be a fluorophore, a protein labeled fluorophore, a protein comprising a photooxidizable cofactor, a protein comprising another intercalated fluorophore; a mitochondrial vital stain or dye, a dye exhibiting at least one of a redox potential, a membrane localizing dye, a dye with energy transfer properties, a pH indicating dye; a coumarin dye, a derivative of a coumarin dye, an anthraquinone dye, a cyanine dye, an azo dye, a xanthene dye, an arylmethine dye, a pyrene derivative dye, or a ruthenium bipyridyl complex dye. [0016] Examples of suitable mitochondrial vital stains or dyes include, but are not limited to, a polycyclic aromatic hydrocarbon dye, such as, for example, rhodamine 123; di-4-ANEPPS; di-8-ANEPPS; DiBAC.sub.4(3); RH421; tetramethylrhodamine ethyl ester, perchliorate; tetramethylrhodamine methyl ester, perchlorate; 2-(4-(dimethylamino)styryl)-N-ethylpyridinium iodide; 3,3'-dihexyloxacarbocyanine, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine chloride; 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarboc- yanine iodide; nonylacridine orange; dihydrorhodamine 123 dihydrorhodamine 123, dihydrochloride salt; xanthene; 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein; benzenedicarboxylic acid; 2(or 4)-[10-(dimethylamino)-3-oxo-3-H-benzo[c]xanthene-7-yl]; and iodine dissolved in potassium iodide. [0017] Examples of suitable protein labeled fluorophores include, but are not limited to, Glucose Oxidase-Labeled Fluorophore (GO-LF) and Glucose Oxidase-Intercalated Fluorophore (GO-IF). Examples of a suitable protein include a photooxidizable cofactor includes Glucose Oxidase (GOx) with a flavin adenine dinucleotide (FAD) in the triplet state (GOx-.sup.3FAD*). [0018] The one or more specific metabolites or analytes to be detected in a surface of living tissue, organs, interstitial fluid, and whole organisms include, for example, glucose, lactate, H.sup.+, Ca.sup.2+, Mg.sup.2+, Na.sup.+, K.sup.+, ATP, ADP, P.sub.i, glycogen, pyruvate, NAD(P)+, NAD(P)H, FAD, FADH.sub.2, and O.sub.2. [0019] The in vivo information obtained when the SMMR is brought in contact with the one or more metabolites or analytes can include, but is not limited to, assessment of metabolic function; diagnosis of metabolic disease state; monitoring and control of disease state; stress status of cells, tissues and organs; determination of vitality and viability of cells based on metabolic function; critical care monitoring; diagnosis and monitoring of cardiovascular diseases, autoimmune disorders, neurological disorders, degenerative diseases; determination of metabolic concentration; and cancer diagnosis, detection, staging and prognosis. [0020] For example, the in vivo information obtained may provide detailed information on glucose metabolism, fructose metabolism and galactose metabolism; advanced-glycosolated end products; monitoring and control of diseases such as diabetes, cancer, stress and organ transplantation. Continue reading about Non-invasive measurement of analytes... 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